In contrast to HIV-infected individuals, sooty mangabeys (SMs), an African monkey species that is a natural host for SIV, live an apparently normal lifespan in captivity despite many years of SIV infection. Although SMs are typically infected with a highly replicating virus, only a subset (10-15%) display moderate to severe CD4+ T cell depletion and, in fact, the development of an AIDS-like illness is very rare. The aim of this project is to understand how SIV-infected SMs maintain CD4+ T cell homeostasis and avoid progression to AIDS. We will perform comparative studies of SIV-infected SMs with normal and depleted CD4+ T cell compartments. Pathogenic SIV infection of rhesus macaques (RMs), a non-natural host Asian monkey species, will also be used as a comparative model. The proposed studies will test three fundamental hypotheses that may explain why SIV infection of SMs is significantly less pathogenic than HIV infection of humans and SIV infection of RMs: (i) the average lifespan of virus infected cells is longer (and/or the fraction of virus produced by long-lived cells is higher);(ii) the infection is associated with lower levels of T cell turnover;and (iii) the virus infects a more limited subset of CD4+ T cells. The results of these studies will improve our understanding of the mechanisms underlying the lack of disease in SIV-infected SMs. These conceptual advances may provide insights for the pathogenesis of HIV infection in humans and may translate into the design of more effective treatments for AIDS.